Abstract: Neurodegenerative diseases are characterized by the misprocessing of specific proteins, but how and if this results in cell death has been unknown. This proposal supports collaborative research between immunology and neuroscience laboratories with disease experts to pursue new findings that require such cross-disciplinary collaboration. Our joint Preliminary Results provide the first direct evidence that Parkinson's disease (PD), which has long been known to feature prominent neuroinflammatory components, is for at least many patients in part an autoimmune disorder that features antigen presentation and specific T cell responses. The results demonstrate that PD shares fundamental features with classical autoimmune disorders including Type-1 diabetes, multiple sclerosis, and rheumatoid arthritis. Our overall hypothesis is that PD is associated with self- derived neoantigens that becomes increasingly expressed in aging or disease conditions. Our overall aim is to identify the antigenic responses associated with PD and Alzheimer's disease (AD). We will identify ?-synuclein-derived and tau-derived neoantigens in these patients and compare these profiles in patients with PD, AD, age-matched controls and young controls. We will 1) identify epitopes that act as neoantigens in PD and AD; 2) characterize the responsive T cells; 3) characterize the role of antigen presentation and T cell- mediated neuronal death by animal models that express an HLA allele implicated in PD with high affinity to an ?-syn epitope. If the autoimmune features are confirmed, therapies used to treat other autoimmune disorders such as tolerization can be used to treat PD.